Development of NEO212, A Novel Oral Drug for the Treatment of Acute Myeloid Leukemia

Project Summary First-line treatment of patients with acute myeloid leukemia (AML) is primarily based on the use of cytarabine C (AraC), either alone or combined with other drugs. However, relapsed and refractory disease is common and significantly worsens prognosis, despite complex interventions at this stage that may include bone marrow transplantation. Better treatments are urgently needed. We are developing NEO212, a novel anticancer small molecule. It was created by covalent conjugation of two well-characterized anticancer agents, perillyl alcohol (POH, a naturally occurring monoterpene related to limonene) and temozolomide (TMZ, an alkylating agent in clinical use for malignant glioma therapy). In mouse models of AML, NEO212 was highly effective to the point where long-term survival of mice was achieved, suggesting curative outcomes. This was also the case with strongly AraC-resistant AML variants. As important, NEO212 treatment was very well tolerated and mice did not reveal any toxic side effects of drug treatment. Based on these encouraging results, the overall goal of our project is to perform studies toward an IND (investigational new drug) submission to the FDA, so that the promise of better treatments of AML through NEO212 therapy can be validated in clinical trials. We hypothesize that the striking anticancer activity of NEO212—and its well-tolerated nature—is derived from its two-component composition that generates binary, synergistic impact preferentially on tumor cells. Conjugation to POH enables substantially increased cell entry of TMZ. Inside the cell, POH aggravates endoplasmic reticulum (ER) stress, which pre-exists in leukemia cells and provides a tumor-specific target. Increased ER stress is known to sensitize tumor cells to alkylating agents, in this case, TMZ. Aggravated ER stress, combined with DNA damage by DNA methylation, results in tumor cell apoptosis. Of note, this synergistic effect cannot be achieved with combination treatment of individual components, i.e., POH merely mixed with TMZ, because conjugation of POH is required to enable cell entry of sufficiently high amounts of TMZ. Our specific aims are: (1) To establish the veracity of our hypothesis concerning the mechanism by which NEO212 achieves its striking anticancer activity, namely that tumor-specific ER stress is aggravated by its POH subunit and enables synergistic, pro-apoptotic effects of DNA methylation by its TMZ subunit. (2) To establish and characterize in vivo anti-leukemic potency of NEO212 in primary patient-derived AML samples and in AML stem cell models after implantation into NSG mice, along with PK analysis. The above laboratory work will be complemented by the assembly of paperwork, including the design of a clinical trial in refractory/relapsed leukemia patients, for an investigational new drug (IND) application to the FDA.